Type 2 diabetes is an increasing public health problem affecting ~20 million Americans and is commonly associated with insulin resistance. The insulin-like growth factor (IGF)-I shares structural homology with insulin and increasing evidence indicates that IGF-I and its binding proteins (IGFBPs) may play an important role in normal glucose homeostasis. Exogenous IGF-I administration improves insulin sensitivity in humans, including patients with type 2 diabetes. However, to our knowledge, only one small study has prospectively investigated the association between IGF-I and the risk of developing glucose intolerance and reported that high IGF-I levels were associated with reduced risk of impaired glucose tolerance (IGT) and type 2 diabetes. Although this study provided important initial data, it was limited by its small sample size (44 incident cases of IGT and 7 of type 2 diabetes) and failure to measure `free'IGF-I (possibly the more bioavailable form of IGF-I), as well as IGFBP-2 and IGFBP-3, the two most abundant IGF-binding proteins. The possible importance of measuring all major IGFBPs was suggested in two pilot studies that we conducted within the Women's Health Initiative Observational Study (WHI-OS) and the Cardiovascular Health Study (CHS). In the WHI-OS, IGFBP-3 had a statistically significant positive association with prevalence of impaired fasting glucose and type 2 diabetes, and in the CHS a similar association with type 2 diabetes of borderline statistical significance was observed (IGFBP-2 was not measured). Further, IGF-I may also have anti- inflammatory effects that may lower levels of inflammatory factors associated with insulin resistance and the risk of developing type 2 diabetes. However, the inter-relationships of IGF-I and its binding proteins with inflammatory factors and adipokines are not well understood. This application proposes the first large prospective study to evaluate the associations between fasting plasma levels of total IGF-I, free IGF-I, IGFBP- 1, IGFBP-2 and IGFBP-3 at baseline and risk of incident type 2 diabetes. Specifically, the proposed study will build upon an existing nested case-control investigation of several biomarkers, including inflammatory markers and adipokines, and the risk of type 2 diabetes (900 incident cases and 900 individually matched controls), within the Nurse's Health Study (NHS), a large cohort of women aged 30-55 years at recruitment. The large sample size, long-term follow-up and high quality covariate data, are advantages of this NHS ancillary study. The proposed study also provides a unique and cost-effective opportunity to investigate the inter-relationships of IGF-I and its binding proteins with inflammatory markers and adipokines. If an association between the IGF- axis and type 2 diabetes exists, the relevant components of the IGF-axis could potentially be exploited as targets for novel therapeutic interventions to delay or prevent type 2 diabetes among high-risk individuals. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is an increasing public health problem affecting ~20 million Americans. The proposed study will be the first large prospective study to evaluate the association of the insulin-like growth factor (IGF)-axis and risk of type 2 diabetes. The IGF-axis may potentially play a role in the etiology of type 2 diabetes and its related conditions and may also provide a novel therapeutic target for its prevention.